CN1870980B - 控释无菌阿立哌唑注射剂和方法 - Google Patents
控释无菌阿立哌唑注射剂和方法 Download PDFInfo
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- CN1870980B CN1870980B CN2004800308144A CN200480030814A CN1870980B CN 1870980 B CN1870980 B CN 1870980B CN 2004800308144 A CN2004800308144 A CN 2004800308144A CN 200480030814 A CN200480030814 A CN 200480030814A CN 1870980 B CN1870980 B CN 1870980B
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- aripiprazole
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- aseptic
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Abstract
提供了控释无菌冻干阿立哌唑制剂,所述制剂由具有所需的平均粒度的阿立哌唑及其载体构成,其与水组合并肌肉内注射后,在至少大约1周、多达大约8周的时间期间释放阿立哌唑。也提供了制备控释冻干阿立哌唑制剂的方法和应用上述制剂治疗精神分裂症的方法。
Description
技术领域
本申请要求美国临时申请60/513,618的优先权,该申请的全部公开内容在此并入,作为参考。
本发明涉及控释无菌冻干阿立哌唑制剂(controlled release sterilefreeze-dried aripiprazole formulation),其为注射剂(injectable formulation),含有无菌冻干阿立哌唑并在至少1周期间释放阿立哌唑,也涉及制备上述制剂的方法和应用上述制剂治疗精神分裂症以及相关疾病的方法。
背景技术
授予Oshiro等人的美国专利5,006,528公开了7-[(4-苯基哌嗪)-丁氧基]喹诺酮,其包括阿立哌唑(aripiprazole),其作为多巴胺能神经递质拮抗剂。
具有下列结构的阿立哌唑是用于治疗精神分裂症的非典型抗精神病制剂。它在水中的溶解度低(室温下<1μg/mL)。
授予Liversidge等人的美国专利6,267,989公开了防止纳米颗粒组合物(nanoparticulate compositions)中晶体生长(crystal growth)和粒子聚集(particleaggregation)的方法,其中应用水磨技术(aqueous milling techniques)包括球磨(ballmilling)使纳米颗粒组合物降低为优化有效的平均粒度(average particle size)。
授予Midler等人的美国专利5,314,506涉及直接结晶具有高纯度和稳定性的高表面积颗粒的药物的方法,其中用碰撞射流(impinging jet streams)使药物粒子达到高强度的微混合(micromixing),随后形成晶核并直接生成小晶体。
长效(long-acting)阿立哌唑无菌注射剂作为药物剂型的价值在于,它在精神分裂症的治疗中,可以增加患者的依从性并从而降低复发率。治疗精神分裂症的已知长效药物产品的例子包括癸酸氟哌啶醇和氟奋乃静癸酸酯,两者均有溶解于芝麻油的低水溶解度的酯化合物。含有利培酮(Risperidone)(WO95/13814)和奥氮平(Olanzapine)(WO99/12549)的微胶囊(Microcapsules)也是已知的。
发明概述
根据本发明,提供了无菌冻干阿立哌唑制剂,其与水组合用于注射,在至少大约1周期间,优选地在2周、3周或4周,多达6周期间或更长的时间期间释放出治疗量的阿立哌唑。本发明的冻干阿立哌唑制剂含有:
(a)阿立哌唑,和
(b)阿立哌唑的载体,
该制剂在与水组合(constitution with water)后,形成可注射的悬浮液,在注射后,优选地肌肉内(intramuscularly)注射后,所述悬浮液在至少大约1周期间,优选地在2周、3周或4周,多达6周期间或更长的时间期间释放出治疗量的阿立哌唑。
本发明的冻干阿立哌唑制剂将优选地含有:
(a)阿立哌唑,
(b)一种或多种助悬剂(suspending agents),
(c)任选地一种或多种填充剂(bulking agents),
(d)任选地一种或多种缓冲液,和
(e)任选地一种或多种pH调节剂(pH adjusting agents)。
在配制注射剂时,平均粒度为大约1至大约30微米的冻干阿立哌唑制剂是必需的,所述制剂在至少大约1周的时间,多达6周的时间或更长的时间例如多达8周的时间期间释放阿立哌唑。
已经发现,冻干阿立哌唑的平均粒度越小,延长释放的时间越短。因此,根据本发明,当平均粒度是大约1微米时,阿立哌唑将在少于大约3周,优选地大约2周的时间期间被释放。当平均粒度大于大约1微米时,阿立哌唑将在至少2周期间,优选地大约3至4周期间,多达6周或更长的时间期间被释放。因此,根据本发明,可以通过改变冻干制剂中阿立哌唑的粒度来改变阿立哌唑释放的持续时间。
术语“平均粒度(mean particle size)”是指,如激光光散射(LLS)方法所测定的体积平均径(volume mean diameter)。粒度分布(particle size distribution)是LLS方法测定的,平均粒度是从粒度分布计算出来的。
此外,根据本发明,提供了无菌悬浮液形式的控释无菌可注射阿立哌唑制剂,即,提供了悬浮于注射用水中的本发明冻干制剂,当其被注射后,优选地肌肉内注射后,在至少1周的时间期间释放治疗量的阿立哌唑,所述制剂含有:
(a)阿立哌唑,
(b)其载体,和
(c)用于注射的水。
无菌悬浮液形式的本发明控释无菌可注射制剂,允许每单位体积的制剂有高的药物荷载(drug loading),并因此允许以小的注射体积传送相对高剂量的阿立哌唑(每1mL悬浮液0.1-600mg药物)。
进一步地,根据本发明,提供了制备上述无菌冻干阿立哌唑制剂的方法,包括下列步骤:
(a)制备无菌的阿立哌唑本体(bulk aripiprazole),其优选地具有期望的粒度分布,平均粒度在从大约5至大约100微米的范围内,
(b)制备用于无菌阿立哌唑本体的无菌载体,
(c)使无菌阿立哌唑本体和无菌载体结合,形成无菌的初步悬浮液(sterile primarysuspension),
(d)使无菌初步悬浮液中的阿立哌唑平均粒度降低为大约1至大约30微米范围内,形成最终的无菌悬浮液(final sterile suspension),和
(e)冻干最终的无菌悬浮液,形成具有期望的多晶型(polymorphic form)的阿立哌唑无菌冻干制剂(无水、一水合物或两者的混合物)。
在实施上述方法时,应用无菌湿磨法(aseptic wet milling procedure),优选地是无菌湿球磨(aseptic wet ball milling),使无菌初步悬浮液的平均粒度降低为所需的平均粒度。无菌湿磨在形成均一和无菌的具有所需平均粒度分布的阿立哌唑制剂中是必需的。
此外,根据本发明,提供了冻干最终的无菌阿立哌唑悬浮液的方法,该方法产生所需多晶型的无菌冻干阿立哌唑,其为无水的、一水合物或两者的混合物。
再进一步,根据本发明,提供了治疗精神分裂症和相关疾病的方法,包括将治疗量的上述控释阿立哌唑注射剂给予需要治疗的患者的步骤。
出乎意料地发现,当通过注射——优选地肌肉内注射——被给予时,悬浮于含水溶剂体系的阿立哌唑的悬浮液将维持基本上不变的药物血浆浓度。没有观察到大的“爆发现象”(burst phenomenon),并且令人非常吃惊的是,应用本发明的阿立哌唑悬浮液,可以维持固定不变的阿立哌唑药物血浆浓度一(1)周至多于八(8)周。口服施用阿立哌唑制剂的日起始剂量是十五(15)毫克。为了给予等同于一(1)周至多于八(8)周的口服剂量的药物剂量,需要以单次剂量给予非常大量的药物。本发明的含水阿立哌唑注射剂可以被给予以释放大量药物而不产生患者依从性问题(patient compliance problems)。
本发明的阿立哌唑注射剂可以包括无水或一水合物形式的阿立哌唑或含有两者的混合物。如果一水合物被应用,延时的(extended)药物血浆浓度可能被维持。
本发明的阿立哌唑注射剂可以作为含水的可直接应用(ready-to-use)的悬浮液而被给予,然而,提供冻干此悬浮液,可以提供更有用的药物产品。
附图说明
图1是描述在大鼠中,本发明实施例1制剂的平均血浆浓度与时间关系的图。
图2是描述在犬中,本发明实施例1制剂的平均血浆浓度与时间关系的图。
图3是描述在人中,本发明实施例1制剂的平均血浆浓度与时间关系的图。
发明详述
本发明的控释无菌阿立哌唑注射剂将包括在大约1至大约40%,优选地大约5至大约20%,更优选地大约8至大约15%范围内的阿立哌唑量,这是基于无菌注射剂的重量按重量计算的。
如所指出的,期望的阿立哌唑平均粒度在制备具有期望的控释性质的阿立哌唑注射剂中是必需的。因此,为了产生期望的控释,阿立哌唑的平均粒度应该在大约1至大约30微米范围内,优选地大约1至大约20微米范围,更优选地大约1至大约10至15微米范围。
当期望的控释时间是至少大约2周,多达6周或更长,优选地大约3周至大约4周时,阿立哌唑的平均粒度的范围为大约1至大约20,优选地大约1至大约10微米,更优选地从大约2至4微米,最优选地是大约2.5微米。平均粒度为大约2.5微米的阿立哌唑将具有如下的粒度分布(particle size distribution):
优选的 更优选的
95%<20微米 95%<8微米
90%<15微米 90%<6微米
50%<10微米 75%<3微米
10%<2微米 50%<1.5微米
10%<0.5微米
本发明的阿立哌唑制剂将优选地由下列构成:
A.阿立哌唑
B.其载体,包括:
(a)一种或多种助悬剂,
(b)一种或多种填充剂,
(c)一种或多种缓冲液,和
(d)任选地一种或多种pH调节剂。
助悬剂的存在量按重量计将是从大约0.2至大约10%,优选地大约0.5至大约5%,这是基于无菌注射剂的总重量而言的。适于应用的助悬剂的例子包括但不限于下列中的一种、两种或更多种:羧甲基纤维素钠、羟丙基纤维素、羧甲基烯酸、羟丙基乙基纤维素、羟丙基甲基纤维素和聚乙烯吡咯烷酮,优选羧甲基纤维素钠和聚乙烯基吡咯烷酮。适于在阿立哌唑载体中使用的其它助悬剂包括各种聚合物、低分子量寡聚物、天然产物和表面活性剂,包括非离子表面活性剂和离子表面活性剂,如氯化十六烷基吡啶、明胶、酪蛋白、卵磷脂(磷脂)、葡聚糖、甘油、阿拉伯树胶、胆固醇、黄芪胶、硬脂酸、苯扎氯铵、硬脂酸钙、单硬脂酸甘油酯、十八十六醇(cetostearyl alcohol)、聚西托醇乳化蜡(cetomacrogol emulsifyingwax)、失水山梨醇酯、聚氧乙烯烷基醚(例如,聚乙二醇醚如聚西托醇1000)、聚氧乙烯蓖麻油衍生物、聚氧乙烯失水山梨醇脂肪酸酯(例如,商业上可得到的如和(ICI Specialty Chemicals));聚乙二醇(例如,Carbowaxs和和Carbopol(Union Carbide))、溴化十二烷基三甲胺、聚氧乙烯硬脂酸酯、胶体二氧化硅、磷酸酯、十二烷基硫酸钠、羧甲基纤维素ti钙(carboxymethylcellulose ti calcium)、羟丙基纤维素(例如,HPC、HPC-SL和HPC-L)、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、非晶体纤维素、硅酸铝镁、三乙醇胺、聚乙烯醇(PVA)、带有环氧乙烷和甲醛的4-(1,1,3,3-四甲基丁基)-酚聚合物(也称为泰洛沙泊、superione和triton),poloxamers(例如,Pluronics和其为环氧乙烷和环氧丙烷的嵌段共聚物);poloxamines(例如,Tetronic也称为Poloxamine其为将环氧丙烷和环氧乙烷顺序加至乙二胺而形成的四功能嵌段共聚物(BASF Wyandotte Corporation,Parsippany,N.J.));带电荷磷脂如双肉豆蔻酰磷脂酰甘油、琥珀酸二辛酯磺酸盐(DOSS);Tetronic(T-1508)(BASF Wyandotte.Corporation)、磺基琥珀酸钠的二烷基酯(例如Aerosol其为磺基琥珀酸钠的二辛酯(American Cyanamid));其为月桂硫酸钠(DuPont);Tritons它是烷基芳基聚醚磺酸酯(Rohm and Haas);Crodestas其为蔗糖硬脂酸酯和蔗糖二硬脂酸酯的混合物(Croda Inc.);p-异壬基苯氧基聚-(环氧丙醇),也称为或Surfanctant(Olin Chemicals,Stamford,Conn.);Crodestas(Croda,Inc.);和SA90HCO,其为C18H37CH2(CON(CH3))-CH2(CHOH)4(CH2OH)2(Eastman KodakCo.);癸酰基-N-甲基葡糖酰胺;n-癸基β-D-吡喃葡糖苷;n-癸基β-D吡喃麦芽糖苷;n-十二烷基β-D-吡喃葡糖苷;n-十二烷基β-D-麦芽糖苷;庚酰基-N-甲基葡糖酰胺;n-庚基-β-D-吡喃葡糖苷;n-庚基β-D-硫代葡糖苷;n-己基β-D吡喃葡糖苷;壬酰基-N-甲家葡糖酰胺;n-壬基β-D-吡喃葡糖苷;辛酰-N-甲基葡糖酰胺;n-辛基-β-D-吡喃葡糖苷;辛基β-D-硫代吡喃葡糖苷;和类似物。
这些助悬剂中的大多数是已知的药物赋形剂,在Handbook ofPharmaceutical Excipients中详细描述,该书由American Pharmaceutical Association和The Pharmaceutical Society of Great Britain联合出版(The Pharmaceutical Societyof Great Britain(The Pharmaceutical Press,1986),明确将该书并入作为参考。悬浮剂是商业上可得到的和/或可以通过本领域中的已知技术制备。
当期望的平均粒度是大约1微米或以上时,特别优选羧甲基纤维素或其钠盐。
填充剂(也称为低温/冻干保护剂)的存在量按重量计将是大约1至大约10%,优选地从大约3至大约8%,更优选大约4至大约5%的范围,这是基于无菌注射剂的总重量而言的。适于此处用途的填充剂的例子包括但不限于下列中的一种、两种或更多种:甘露醇、蔗糖、麦芽糖、木糖醇、葡萄糖、淀粉、山梨醇、和类似物,对于平均粒度是大约1微米或以上的制剂,优选甘露醇。发现木糖醇和/或山梨醇通过抑制晶体生长和药物颗粒的结块而增强阿立哌唑制剂的稳定性,以致于可以得到并保持所需的粒度。
缓冲液的使用量将调节阿立哌唑冻干制剂的含水悬浮液的pH值为大约6至大约8,优选大约7。为了达到所述pH,通常地,根据缓冲液的类型,缓冲液的使用量的范围按重量计是从大约0.02至大约2%,优选从大约0.03至大约1%,最优选大约0.1%,这是基于无菌注射剂的总重量而言的。适于此用途的缓冲液的例子包括但不限于下列中的一种、两种或多种:磷酸钠、磷酸钾或TRIS缓冲液,优选磷酸钠。
本发明的冻干制剂可以任选地包括pH调节剂,其使用量可以调节冻干阿立哌唑的含水悬浮液的pH值在大约6至大约7.5的范围,优选大约7,根据冻干阿立哌唑的含水悬浮液的pH值是否需要升高或降低以达到所需的大约7的中性pH,pH调节剂可以是酸性的或碱性的。因此,当需要降低pH时,可以应用酸性pH调节剂如盐酸或醋酸,优选盐酸。当需要升高pH时,将应用碱性pH调节剂如氢氧化钠、氢氧化钾、碳酸钙、氧化镁或氢氧化镁,优选氢氧化钠。
冻干阿立哌唑制剂可以和一定量的注射用水组合,提供大约10至大约400mg的阿立哌唑,以2.5mL或更少,优选2mL的体积输送,用作2至6周的剂量。
在实施制备本发明冻干阿立哌唑制剂的方法中,要求所有物质为无菌,这样,无菌阿立哌唑和无菌载体无菌结合,形成无菌悬浮液,并且无菌悬浮液以形成无菌冻干粉末或饼块的形式被冻干。因此,应用无菌方法来产生具有所需粒度分布的无菌阿立哌唑本体。无菌阿立哌唑本体的平均粒度将在大约5至大约100微米,优选大约10至大约90微米的范围内。
优选地,应用连续的加工过程(continuous processing),用碰撞射流结晶法(impinging jet crystallization method)产生具有所需小的粒度和窄的粒度分布、高的表面积、高化学纯度、由于晶体结构改进而具有高稳定性的无菌阿立哌唑。
碰撞射流结晶方法利用彼此迎面碰撞的两股射流(jet streams)。一股流携带富含阿立哌唑的溶液,另一股流携带反溶剂(anti-solvent)如水。两股流彼此碰撞,由于碰撞时的高度湍流和高强度的微混合,使得快速均匀混合和过度饱和(supersaturation)。这种立即得到的过度饱和起始了快速的晶核形成。一般而言,随着渐增的过度饱和减降的反溶剂温度,平均晶体大小降低。因此,为了得到最小粒度,有利的是,具有最高可能浓度的富含溶液和最低温度的反溶剂。
制备无菌阿立哌唑本体的载体,其包括助悬剂、填充剂、缓冲液、任选的pH调节剂和水,并使之无菌。此后,使无菌的阿立哌唑本体和无菌载体无菌结合,形成无菌初步悬浮液并使阿立哌唑的粒度降低至所需水平。这优选应用无菌湿磨法进行,其中分散于无菌载体中的阿立哌唑无菌颗粒在研磨介质存在下用研磨方法处理,使阿立哌唑的粒度降低为大约1至大约10微米,这取决于所需的控释时间。
无菌湿磨法优选湿球磨。当所需阿立哌唑平均粒度是大约1微米以上时,以大约5至大约15L/hr,优选大约8至大约12L/hr,最优选大约10L/hr,使初步悬浮液(结合的阿立哌唑-载体)穿过湿球磨机(wet ball mill)一次(单次通过),以使阿立哌唑的平均粒度降低至所需范围内,例如,大约1至大约5微米。
除了球磨机例如Dyno研磨机(mills)之外,可以应用其它低能和高能研磨机如辊磨机(roller mill),可以用高能研磨机如Netzsch研磨机、DC研磨机和Planetary研磨机。然而,应用的研磨方法和设备必须能够产生具有所需平均粒度的无菌阿立哌唑制剂。
可以应用其它降低粒度的技术,包括无菌的受控结晶、高剪切匀浆(highshear homogenization)、高压匀浆和微流化(microfluidization),以产生平均粒度范围为大约1至大约100微米的颗粒。
将得到的最终悬浮液无菌填充入无菌瓶内并无菌加载入无菌冻干器。为了形成和/或维持阿立哌唑的所需晶型,需要应用谨慎设计的冷冻干燥循环,已知所述阿立哌唑以一水合物形式(阿立哌唑水合物A)以及大量的无水形式存在,即无水晶体B、无水晶体C、无水晶体D、无水晶体E、无水晶体F和无水晶体G,所有的形式都可以用于本发明制剂。
用于本发明的阿立哌唑一水合物(颗粒)或如下面提及的水合物具有下面的(1)-(5)所指出的理化性质。阿立哌唑水合物此后描述为“阿立哌唑水合物A”。
(1)它的吸热曲线特征是,在大约71℃有一个小峰,在60℃至120℃附近有渐进的吸热峰。
(2)它的′H-NMR谱具有如下特征峰:1.55-1.63ppm(m,2H)、1.68-1.78ppm(m,2H)、2.35-2.46ppm(m,4H)、2.48-2.56ppm(m,4H+DMSO)、2.78ppm(t,J=7.4Hz,2H)、2.97ppm(brt,J=4.6Hz,4H)、3.92ppm(t,J=6.3Hz,2H)、6.43ppm(d,J=2.4Hz,1H)、6.49ppm(dd,J=8.4Hz,J=2.4Hz,1H)、7.04ppm(d,J=8.1Hz,1H)、7.11-7.17ppm(m,1H)、7.28-7.32ppm(m,2H)和10.00ppm(s,1H)。
(3)它的粉末x-线衍射光谱在下列处具有特征峰:2θ=12.6°、15.4°、17.3°、18.0°、18.6°、22.5°和24.8°。
(4)它在下列处具有清楚的红外吸收带:IR(KBr)光谱的295l、2822、1692、1577、1447、1378、1187、963和784cm-1。
(5)它的平均颗粒大小(mean grain size)是50μm或更少。
阿立哌唑水合物A是通过研磨常规的阿立哌唑水合物得到的。
可以用常规的研磨方法研磨阿立哌唑水合物。例如,可以在研磨机中研磨阿立哌唑水合物。可以使用广泛应用的研磨机,如喷雾器、针磨机、射流研磨机(jet mill)或球磨机。其中,优选喷雾器。
关于应用喷雾器时的具体研磨条件,主轴的角速度(rotational speed)可以是5000-15000rpm,例如进料转速(feed rotation)是10-30rpm和筛孔大小是1-5mm。
通过研磨得到的阿立哌唑水合物A的平均颗粒大小通常应该是50μm或更少,优选30μm或更少。可以用此后描述的颗粒大小测定方法确认平均颗粒大小。
颗粒大小测定:在0.5克大豆卵磷脂的20ml正己烷溶液中悬浮欲测定的0.1克颗粒,用粒度分布测量仪(Microtrack HRA,Microtrack Co.)测定颗粒大小。
用于本发明的阿立哌唑无水晶体具有下面(6)-(10)中给出的理化性质。这些阿立哌唑无水晶体此后被称作“阿立哌唑无水晶体B”。
(6)它们的′H-NMR谱(DMSO d6,TMS)具有如下特征峰:1.55-1.63ppm(m,2H)、1.68-1.78ppm(m,2H)、2.35-2.46ppm(m,4H)、2.48-2.56ppm(m,4H+DMSO)、2.78ppm(t,J=7.4Hz,2H)、2.97ppm(brt,J=4.6Hz,4H)、3.92ppm(t,J=6.3Hz,2H)、6.43ppm(d,J=2.4Hz,1H)、6.49ppm(dd,J=8.4Hz,J=2.4Hz,1H)、7.04ppm(d,J=8.1Hz,1H)、7.11-7.17ppm(m,1H)、7.28-7.32ppm(m,2H)和10.00ppm(s,1H)。
(7)它们的粉末x-线衍射光谱在下列处具有特征峰:2θ=11.0°、16.6°、19.3°、20.3°和22.1°。
(8)它们在下列处具有清楚的红外吸收带:IR(KBr)光谱的2945、2812、1678、1627、1448、1377、1173、960和779cm-1。
(9)在热重/差示热分析(加热速度是5℃/min)中,它们在大约141.5℃附近显示了吸热峰。
(10)在差示扫描量热法(加热速度是5℃/min)中,它们在大约140.7℃附近显示了吸热峰。
用于本发明的阿立哌唑无水晶体B具有低吸湿性。例如,用于本发明的阿立哌唑无水晶体B,在设置温度是60℃、湿度是100%的干燥器中24小时之后,维持0.4%或更少的水含量。
可以应用测定水含量的已知方法,只要是测定晶体水含量的常规方法即可。例如,可以应用方法如Karl Fischer方法。
通过例如在90-125℃加热前述的阿立哌唑水合物A,制备本发明的阿立哌唑无水晶体B。加热时间通常是大约3-50小时,这取决于加热温度。加热时间和加热温度是负相关的,因此,例如,加热温度越低,加热时间将越长,加热温度越高,加热时间越短。具体来说,如果阿立哌唑A的加热温度是100℃,加热时间将通常是18小时或更长或优选地大约24小时。另一方面,如果阿立哌唑水合物A的加热温度是120℃,加热时间可以是大约3小时。通过于100℃加热阿立哌唑水合物A大约18小时,随后在120℃加热大约3小时,必然可以制备本发明的阿立哌唑无水晶体B。
而且,例如,通过于90-125℃加热常规的阿立哌唑无水晶体,制备用于本发明的阿立哌唑无水晶体B。加热时间通常是大约3-50小时,这取决于加热温度。如上所述,加热时间和加热温度是负相关的。具体来说,如果阿立哌唑无水晶体的加热温度是100℃,加热时间可以是大约4小时,如果加热温度是大约120℃,加热时间可以是大约3小时。
阿立哌唑无水晶体的是通过例如下面的方法a或b制备的,所述阿立哌唑无水晶体是制备本发明中应用的阿立哌唑无水晶体B的原材料。
方法a:
通过已知方法制备阿立哌唑无水晶体B,如日本未审的专利公开号191256/1990的实施例1所描述,通过使7-(4-溴丁氧基)-3,4-二氢喹诺酮和1-(2,3-二氯苯基)哌啶反应并使得到的阿立哌唑粗提晶体和乙醇重结晶。
方法b:
通过在至少60℃并低于90℃的温度下加热常规的阿立哌唑水合物,制备阿立哌唑无水晶体B。加热时间通常是大约1-30小时,这取决于加热温度。如上所述,加热时间和加热温度是负相关的。具体来说,如果阿立哌唑水合物的加热温度是大约60℃,加热时间可以是大约8小时,而如果加热温度是80℃,加热时间可以是大约4小时。
方法b描述于第四次日韩分离技术研讨会(Japanese-Korean Symposiumon Separation Technology)(十月6-8,1996)会议记录中。
此外,例如通过在90-125℃加热常规的阿立哌唑水合物,制备用于本发明的阿立哌唑无水晶体B。加热时间通常是大约3-50小时,这取决于加热温度。加热时间和加热温度是负相关的。具体来说,如果阿立哌唑水合物的加热温度是大约100℃,加热时间可以是大约24小时,而如果加热温度是120℃,加热时间可以是大约3小时。
阿立哌唑水合物是通过例如下面的方法c制备的,所述阿立哌唑水合物是制备本发明中应用的阿立哌唑无水晶体B的原材料。
方法c:
通过在含水溶剂中溶解上述方法a得到的阿立哌唑无水晶体,并加热和随后冷却得到的溶液,得到阿立哌唑水合物。应用本方法,阿立哌唑水合物在含水溶剂中作为晶体被沉淀出来。
含水的有机溶剂通常被用作含水溶剂。有机溶剂应当是可混溶于水的,如,例如醇如甲醇、乙醇、丙醇或异丙醇,酮如乙酮,醚如四氢呋喃、二甲基甲酰胺,或其混合物,特别期望的是乙醇。含水溶剂中的水的量可以是该溶剂重量的10-25%,或优选地接近20%重量。
如上所述,通过在90-125℃加热阿立哌唑水合物A、常规的阿立哌唑无水晶体或常规的阿立哌唑水合物,制备用于本发明的阿立哌唑无水晶体B,阿立哌唑水合物A、常规的阿立哌唑无水晶体或常规的阿立哌唑水合物可以单独应用或联合应用。
可以用于此处的阿立哌唑的上述晶体形式和其它晶体形式以及制备这些晶体形式的方法包括水合物A和无水晶体B以及无水晶体C、无水晶体D、无水晶体E、无水晶体F和无水晶体G,如2003年4月4日公布的PCTWO 03/26659中所公开。
如果需要冻干制剂中的一水合物形式的阿立哌唑,则冷冻干燥循环应该包括,以合适的冷却速度将制剂冷却至大约-40℃。初步干燥应该在低于大约0℃下和合适的真空及持续时间下实施。
如果需要冻干制剂中的无水形式的阿立哌唑,则冷冻干燥循环应该包括三个阶段:冷冻、初步干燥和二次干燥。冷冻阶段应该包括以合适的冷却速度将制剂冷却至大约-40℃。初步干燥应该在低于大约0℃和合适的真空及持续时间下实施。二次干燥应该在高于大约0℃和合适的真空及持续时间下实施。
在大气压或部分真空下,将带有得到的冻干阿立哌唑悬液的瓶无菌塞住并密封。
优选的含水悬浮液形式的注射剂陈述如下:
优选的粒度是大约1-10微米(优选地是大约2.5微米)
范围%w/v | 优选范围%w/v | |
(1)无菌阿立哌唑一(平均粒度是从大约1至大约5微米) | 1至40 | 8至15 |
(2)助悬剂(优选羧甲基纤维素钠盐) | 0.2至10 | 0.5至5 |
(3)填充剂(优选甘露醇) | 1至10 | 4至5 |
(4)缓冲液(优选磷酸钠)(调节pH至大约6至大约7.5) | 0.02至2 | 0.03至1 |
(5)pH调节剂(优选氢氧化钠)(调节pH至大约6至大约7.5) | 按需要 | 按需要 |
(6)用于注射的水 | 按需要 | 按需要 |
阿立哌唑在含水可注射制剂中的存在量的范围将是从大约1至大约40%(w/v),优选从大约5至大约20%(w/v),更优选从大约8至大约15%(w/v),这是基于总注射制剂而言的。
在优选的实施方案中,阿立哌唑将存在于含水可注射制剂中,提供大约50至大约400mg/2mL的制剂,优选地大约100至大约200mg/mL的制剂。
根据本发明,优选的单独剂量的注射剂如下:
阿立哌唑 | 100mg | 200mg | 400mg |
羧甲基纤维素 | 9mg | 9mg | 9mg |
甘露醇 | 45mg | 45mg | 45mg |
磷酸钠 | 0.8mg | 0.8mg | 0.8mg |
氢氧化钠 | 适量,调节pH为7 | 适量,调节pH为7 | 适量,调节pH为7 |
用于注射的水 | 适量,调节至1mL | 适量,调节至1mL | 适量,调节至1mL |
本发明的阿立哌唑制剂被用于治疗人类患者的精神分裂症和相关疾病如双相性精神障碍和痴呆。用于本发明注射剂的优选剂量将是单次注射或多次注射,其包含大约100至大约400mg阿立哌唑/mL,每月给予一次或两次。尽管皮下注射也可以接受,优选肌肉内给予该注射剂。
下列实施例显示了本发明的优选实施方案。
实施例
实施例1
如下地制备阿立哌唑注射(IM Depot)含水悬浮液(200mg阿立哌唑/2mL,200mg/瓶)。
通过介质研磨制备的阿立哌唑微悬浮液
用-MILL(Type KDL A,Willy A.Bachoffen AG Maschinenfabrik,Basel,Switzerland制造)制备阿立哌唑微颗粒分散体(microparticulate dispersion)。
向保持在15℃(±5℃)的3L玻璃套层容器中加入下列成分,形成无菌的初步悬浮液:
阿立哌唑 100g
羧甲基纤维素,钠盐7L2P 9.0g
甘露醇 45g
磷酸钠盐,一价 0.8g
氢氧化钠溶液,1N 适量,调节pH为7
用于注射的水,USP 适量,至1040g
在20″Hg(±5″Hg)真空下,以50-100rpm混合该初步悬浮液大约0.5小时,随后以300-500rpm再混合1小时。
相应地准备用于介质研磨方法(media milling process)的介质研磨机。使研磨容器部分地充满氧化锆珠子并使分散体穿过研磨机,按下列条件进行操作:
研磨容器 水套0.6L(water jacketed 0.6L)不锈钢容器
冷却温度(coolant temperature) 15℃(±5℃)
搅拌速度(agitation speed) 2500rpm
研磨介质 500mL极高密度(VHD)氧化锆珠子
悬浮液流速 10L/h
研磨时间 6分钟
单次穿过研磨(a single pass millingt)之后,移走处理过的悬浮液的样品,并用Horiba LA-910激光散射粒度分布分析仪(Laser Scattering Particle SizeDistribution Analyzer)评价粒度分布。确定颗粒具有2.5微米(μ)的平均粒度和下列粒度分布:10%<0.4μ,50%<1.6μ,75%<3.3μ,90%<5.9μ,和95%<7.6μ。
将2.5mL的上述悬浮液无菌填充入无菌瓶中,随后用无菌塞子无菌地将其部分塞住。将瓶无菌转移至冷冻干燥器并按下列循环进行冻干:
(a)热处理:于-40℃冷冻产物0.1-1小时,置于-40℃至少3小时,
(b)冷却冷凝器至-50℃或更低,
(c)初步干燥:在大约2小时期间,降低舱压至大约100微米汞柱并升高产物温度至-5℃;于-5℃和100微米汞柱下持续初步干燥至少48小时,
(d)应用无菌氮或空气,在大气压或部分真空下塞住瓶并从冷冻干燥器中移出,
(e)用合适的封口物密封瓶并加上标签。
实施例2
阿立哌唑注射(IM Depot)含水悬浮液(200mg阿立哌唑/2mL,200mg/瓶)制备如下:
通过碰撞射流结晶制备的阿立哌唑微悬浮液
用碰撞射流结晶(impinging jet crystallization)制备阿立哌唑微颗粒分散体。
用下列方法形成无菌阿立哌唑本体(bulk aripiprazole):
1.在2000mL的95%乙醇中悬浮100g的阿立哌唑。加热悬浮液至80℃,直至其变为澄清的溶液。
2.将该阿立哌唑溶液精制过滤(polish filter)到巴氏杀菌保温桶(holding vessel)并维持在80℃。
3.将2000mL水精制过滤到另一巴氏杀菌保温桶并加热至80℃。
4.以0.25kg/min抽吸阿立哌唑溶液使其通过0.02英寸直径的喷嘴,用以0.25kg/min抽吸通过0.02英寸直径喷嘴的30℃水碰撞所述阿立哌唑溶液,形成晶体浆液(sluury),所述浆液收集到碰撞容器(impingement vessel)中。
5.搅拌碰撞容器中新形成的晶体浆液,同时持续将其转移至接受器(receiver),以维持碰撞容器中的容量不变。
6.在碰撞结束时,冷却接受器中的浆液至室温。
7.过滤浆液。
8.于真空下在35℃将湿的饼块干燥,产生100g(96%回收率)的粒度降低的阿立哌唑(90%<100μm)。
将下列成分加入保持在15℃(±5℃)的3L玻璃套层容器内,形成无菌初步悬浮液:
阿立哌唑(经碰撞射流结晶制备) 100g
羧甲基纤维素,钠盐7L2P 9.0g
甘露醇 45g
磷酸钠盐,一价 0.8g
氢氧化钠溶液,1N 适量,调节pH为7
水,USP 适量,至1040g
在20″Hg(±5″Hg)真空下,以500-1000rpm混合无菌悬浮液大约0.5小时,随后以300-500rpm再混合1小时。
发现无菌悬浮液含有平均粒度为2.5微米和下列粒度分布的颗粒:
10%<0.4μ
50%<1.6μ
75%<3.3μ
90%<5.9μ
95%<7.5μ
将2.5mL的上述悬浮液无菌填充入无菌瓶中,随后用无菌塞子无菌地将其部分塞住。将瓶无菌转移至冷冻干燥器并按下列循环进行冻干:
(a)热处理:于-40℃冷冻产品0.1-1小时,置于-40℃至少6小时,
(b)冷却冷凝器至-50℃或更低,
(c)初步干燥:在大约2小时期间,降低舱压至大约100微米汞柱并升高产物温度至-5℃;于-5℃和100微米汞柱下持续进行初步干燥至少48小时,
(d)应用无菌氮或空气,在大气压或部分真空下塞住瓶并从冷冻干燥器中移出,
(e)用合适的封口物密封瓶并加上标签。
实施例3(动物药物代谢动力学(PK)数据)
A.大鼠中单剂量I.M.长效研究(I.M.Depot study)
将实施例1中制备的阿立哌唑I.M.长效制剂注射入十五只大鼠(M-雄性,F-雌性)的大腿肌,剂量是12.5、25和50mg/kg。在第1天(注射后6小时)、2、4、7、10、15、22、28、36和43天收集血液样品,以评价阿立哌唑I.M.长效物给予后的全身性暴露,并分析阿立哌唑。图1显示了大鼠中阿立哌唑的平均血浆浓度对时间的图。
B.犬的单剂量I.M.长效研究
将实施例1中制备的阿立哌唑肌肉内施用(I.M.)长效制剂注射入五只犬(M-雄性,F-雌性)的大腿肌,剂量是100、200和400mg。在第1天(注射后10和30分钟以及1、3和8小时)、2、4、7、10、15、22、28、36和43天收集血液样品,以评价阿立哌唑I.M.长效物给予后的全身性暴露,并分析阿立哌唑。图2显示了犬中的阿立哌唑的平均血浆浓度对时间的图。
PK图
大鼠的阿立哌唑平均血清浓度-时间图以图形显示于图1中。在大鼠模型中,阿立哌唑含水悬浮液显示了至少4周的稳定血清浓度。
犬的阿立哌唑平均血清浓度-时间图以图形显示于图2中。
在犬模型中,阿立哌唑含水悬浮液显示了3-4周的稳定血清浓度。
实施例4(人PK数据)
在患者中的单剂量I.M.长效研究
将实施例1中制备的阿立哌唑I.M.长效制剂肌肉内给予患者,所述患者被诊断为慢性稳定型精神分裂症或分裂情感性障碍。研究设计包括向所有对象给予5mg剂量的阿立哌唑溶液,随后给予单次剂量的IM长效物,每名患者15、50和100mg。收集用于PK分析的样品,直至在连续2次观察中的阿立哌唑血浆浓度低于定量下限(LLQ)。
图3显示了,在给予15mg的I.M.长效剂量的对象2和3中,以及接受50mg的IM长效剂量的对象4和5中,阿立哌唑的平均血浆浓度对时间的图。在所有情况下,阿立哌唑的血浆水平显示出快速的释放发生以及至少30天的延续释放。
Claims (28)
1.无菌悬浮液形式的控释无菌阿立哌唑注射制剂,其在注射后,在至少1周的时间期间释放阿立哌唑,该制剂包括:
(a)阿立哌唑,其具有1至10微米的平均粒度,
(b)其载体,和
(c)用于注射的水,
其中所述注射制剂包括下述量的阿立哌唑,其在基于所述无菌阿立哌唑注射制剂的体积为按重量计1%至40%的范围内。
2.权利要求1所述的制剂,其中所述载体包括一种或多种助悬剂。
3.权利要求1所述的制剂,其中所述阿立哌唑是无水形式或一水合物形式。
4.权利要求3所述的制剂,其中所述阿立哌唑是阿立哌唑无水晶体B或阿立哌唑水合物A的形式。
5.无菌悬浮液形式的控释阿立哌唑注射制剂,其在注射后,在至少1周的时间期间释放阿立哌唑,该制剂包括:
(a)阿立哌唑,其具有1至10微米的平均粒度,
(b)其载体,所述载体包括:
(1)一种或多种助悬剂,
(2)任选地,一种或多种填充剂,和
(3)任选地,一种或多种缓冲剂,以及
(c)用于注射的水,
其中所述注射制剂包括下述量的阿立哌唑,其在基于所述无菌阿立哌唑注射制剂的体积为按重量计1%至40%的范围内。
6.权利要求5所述的制剂,进一步包括pH调节剂。
7.权利要求5所述的制剂,其为无菌悬浮液形式。
8.权利要求5所述的制剂,其为无菌悬浮液形式,所述悬浮液含有平均粒度在2至4微米范围内的阿立哌唑。
9.权利要求8所述的制剂,其中所述阿立哌唑的平均粒度为2.5微米。
10.权利要求5所述的制剂,其为悬浮液形式,其中:
(a)阿立哌唑存在的量在1%至40%范围内,
(b)助悬剂存在的量在0.2%至10%范围内,
(c)填充剂存在的量在2%至10%范围内,
(d)缓冲剂存在的量在0.02%至2%范围内,以调节悬浮液的pH值在6至7.5的范围内,
上述所有百分数是基于悬浮液体积的重量/体积百分数。
11.权利要求5所述的制剂,其中所述助悬剂是羧甲基纤维素或其钠盐、羟丙基纤维素、羧甲基纤维素、羟丙基乙基纤维素、羟丙基甲基纤维素、或聚乙烯吡咯烷酮,所述填充剂是甘露醇、蔗糖、麦芽糖、乳糖、木糖醇或山梨醇,所述缓冲剂是磷酸钠、磷酸钾或TRIS缓冲液。
12.权利要求5所述的制剂,其在注射后,在2周至4周的时间期间释放阿立哌唑,该制剂包括:
(a)阿立哌唑,
(b)羧甲基纤维素或其钠盐,
(c)甘露醇,
(d)磷酸钠,以调节pH为7,
(e)任选地,氢氧化钠,以调节pH为7,和
(f)用于注射的水。
13.权利要求12所述的制剂,包括:含量为100mg、200mg或400mg的阿立哌唑;含量为9mg的羧甲基纤维素;含量为45mg的甘露醇;含量为0.8mg的磷酸钠;适量以便调节pH为7的氢氧化钠;和适量以便补充至1mL的用于注射的水。
14.无菌冻干控释阿立哌唑制剂,其包括:
(a)阿立哌唑,其具有1至10微米的平均粒度,和
(b)其载体,
其中所述制剂在与水组合后,形成无菌悬浮液形式的无菌注射制剂,在注射后,所述无菌注射制剂在至少2周的时间期间释放阿立哌唑,
其中所述注射制剂包括下述量的阿立哌唑,其在基于所述无菌阿立哌唑注射制剂的体积为按重量计1%至40%的范围内。
15.权利要求14所述的冻干制剂,其中所述阿立哌唑具有的平均粒度是2.5微米。
16.权利要求14所述的冻干制剂,其中所述载体包括:
(1)一种或多种助悬剂,
(2)一种或多种填充剂,和
(3)一种或多种缓冲剂。
17.权利要求16所述的冻干制剂,进一步包括pH调节剂。
18.权利要求16所述的冻干制剂,当与水组合并注射后,在至少3周的时间期间释放阿立哌唑,该制剂包括:
(a)阿立哌唑,
(b)羧甲基纤维素或其钠盐,
(c)甘露醇,
(d)磷酸钠以调节pH为7,和
(e)任选地,氢氧化钠以调节pH为7。
19.权利要求18限定的冻干制剂,其中所述阿立哌唑是无水晶体形式或一水合物形式。
20.权利要求14限定的制剂,其中所述阿立哌唑具有在2至4微米范围内的平均粒度。
21.权利要求14限定的制剂,其中所述冻干制剂是饼块的形式。
22.制备权利要求14所述的无菌冻干制剂的方法,包括下列步骤:
(a)制备无菌阿立哌唑本体,
(b)制备用于该无菌阿立哌唑本体的无菌载体,
(c)使所述无菌阿立哌唑和所述无菌载体组合,形成无菌初步悬浮液,
(d)使所述无菌初步悬浮液中的阿立哌唑的平均粒度降低到1至10微米范围内,形成无菌最终悬浮液,和
(e)冻干所述无菌最终悬浮液,形成冻干制剂。
23.权利要求22所述的方法,其中降低所述无菌初步悬浮液中的无菌固体混合物的平均粒度的步骤是用湿磨法实施的。
24.权利要求23所述的方法,其中所述湿磨法包括湿球磨。
25.权利要求22所述的方法,其中所述冻干步骤是通过冷却所述无菌最终悬浮液至-40℃并在低于0℃干燥所述冷却的无菌最终悬浮液来实施的,从而形成一水合物形式的冻干阿立哌唑。
26.权利要求22所述的方法,其中所述无菌最终悬浮液的冻干步骤是以三个阶段实施的:(1)冷冻阶段,包括在-40℃冷却无菌最终悬浮液,(2)初步干燥阶段,在低于0℃进行,和(3)二次干燥阶段,在高于0℃进行,从而形成无水形式的阿立哌唑。
27.如权利要求5所限定的制剂在制备用于治疗精神分裂症的药物中的应用。
28.权利要求27所述的应用,其中所述药物经肌肉内给予或皮下被给予。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019218409A1 (zh) | 2018-05-16 | 2019-11-21 | 丽珠医药集团股份有限公司 | 一种阿立哌唑缓释微球及其制备方法 |
Families Citing this family (68)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR033485A1 (es) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | Sustancia medicinal de aripiprazol de baja higroscopicidad y proceso para la preparacion de la misma |
US20050032811A1 (en) * | 2003-08-06 | 2005-02-10 | Josiah Brown | Methods for administering aripiprazole |
JP4836797B2 (ja) | 2003-10-23 | 2011-12-14 | 大塚製薬株式会社 | 放出制御性無菌注射アリピプラゾール製剤および方法 |
EP1812397A1 (en) * | 2004-11-18 | 2007-08-01 | Synthon B.V. | Process of making crystalline aripiprazole |
EP1933814A2 (en) * | 2005-09-15 | 2008-06-25 | Elan Pharma International Limited | Nanoparticulate aripiprazole formulations |
US8158152B2 (en) * | 2005-11-18 | 2012-04-17 | Scidose Llc | Lyophilization process and products obtained thereby |
DE602006006536D1 (de) * | 2006-01-05 | 2009-06-10 | Teva Pharma | Trockene Aripiprazolformulierungen |
EP2036545A1 (en) | 2006-01-05 | 2009-03-18 | Teva Pharmaceutical Industries Ltd. | Aripiprazole tablets |
TR200604349A2 (tr) | 2006-08-15 | 2008-03-21 | NOBEL İLAÇ SANAYii VE TiCARET A.Ş. | Aripiprazol içeren farmasötik bileşimler |
GB0618879D0 (en) * | 2006-09-26 | 2006-11-01 | Zysis Ltd | Pharmaceutical compositions |
NZ581560A (en) * | 2007-06-25 | 2011-09-30 | Otsuka Pharma Co Ltd | Microspheres having core/shell structure containing aripiprazole |
PL2170279T3 (pl) * | 2007-07-31 | 2018-05-30 | Otsuka Pharmaceutical Co., Ltd. | Sposoby wytwarzania zawiesiny arypiprazolu i liofilizowanej formulacji |
EP3167875A1 (en) | 2009-05-27 | 2017-05-17 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate meloxicam compositions |
KR101125210B1 (ko) * | 2009-09-11 | 2012-03-19 | 주식회사 대웅제약 | 아리피프라졸-벤토나이트-aea 혼성체, 이를 함유하는 약학 조성물 및 그 제조방법 |
CN103284968B (zh) * | 2010-04-13 | 2015-11-18 | 齐鲁制药有限公司 | 一种阿立哌唑组合物微晶的口腔崩解片及其制备方法 |
IL206739A (en) * | 2010-06-30 | 2016-06-30 | David Segal | An injectable drug containing silitol as an active substance |
MX344235B (es) | 2010-08-24 | 2016-12-07 | Otsuka Pharmaceutical Co Ltd * | Suspension y composicion en torta que contiene un derivado de carbostirilo y aceite de silicona y/o un derivado de aceite de silicona. |
CN107625728A (zh) | 2010-10-18 | 2018-01-26 | 大日本住友制药株式会社 | 注射用缓释制剂 |
US9757374B2 (en) * | 2010-10-28 | 2017-09-12 | Aequus Pharmaceuticals Inc. | Aripiprazole compositions and methods for its transdermal delivery |
CA2816203C (en) * | 2010-10-28 | 2017-02-21 | Transdermal Research Pharm Laboratories, Llc | Aripiprazole compositions and methods for its transdermal delivery |
AR083884A1 (es) * | 2010-11-16 | 2013-03-27 | Otsuka Pharma Co Ltd | Jeringa prellenable de doble camara y relleno de aripiprazol en la jeringa |
CN102525915B (zh) * | 2010-12-14 | 2016-09-28 | 江苏豪森药业集团有限公司 | 一种持续释放的注射制剂及其制备方法和用途 |
CN103327968B (zh) | 2011-01-24 | 2016-09-07 | 大塚制药株式会社 | 含有以阿立哌唑作为有效成分的块状组合物的医疗用器具、及以阿立哌唑作为有效成分的块状组合物 |
EP4327872A2 (en) | 2011-03-18 | 2024-02-28 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions comprising sorbitan esters |
JO3410B1 (ar) * | 2011-06-07 | 2019-10-20 | Otsuka Pharma Co Ltd | تركيبة أريبيبرازول مجفف بالتبريد |
CN102850268B (zh) * | 2011-06-27 | 2015-07-15 | 上海中西制药有限公司 | 阿立哌唑ⅰ型微晶、阿立哌唑固体制剂及制备方法 |
WO2013000391A1 (zh) * | 2011-06-27 | 2013-01-03 | 上海中西制药有限公司 | 一种阿立哌唑药物制剂及其制备方法 |
ES2950418T3 (es) | 2012-03-19 | 2023-10-09 | Alkermes Pharma Ireland Ltd | Composiciones farmacéuticas que comprenden alcohol bencílico |
ES2765036T3 (es) | 2012-03-19 | 2020-06-05 | Alkermes Pharma Ireland Ltd | Composiciones farmacéuticas que comprenden esteres de ácidos grasos |
ES2764383T3 (es) | 2012-03-19 | 2020-06-03 | Alkermes Pharma Ireland Ltd | Composiciones farmacéuticas que comprenden ésteres de glicerol |
TWI562991B (en) | 2012-04-23 | 2016-12-21 | Otsuka Pharma Co Ltd | Dihydrate of benzothiophene compound or of a salt thereof, and process for producing the same |
JOP20200109A1 (ar) | 2012-04-23 | 2017-06-16 | Otsuka Pharma Co Ltd | مستحضر قابل للحقن |
AR090775A1 (es) * | 2012-04-23 | 2014-12-03 | Otsuka Pharma Co Ltd | Preparado inyectable |
PT3462173T (pt) | 2012-08-21 | 2021-04-28 | Janssen Pharmaceutica Nv | Anticorpos contra risperidona e utilização dos mesmos |
PT2888284T (pt) | 2012-08-21 | 2022-11-18 | Janssen Pharmaceutica Nv | Anticorpos dirigidos contra haptenos de risperidona e a sua utilização |
EP2888286B1 (en) * | 2012-08-21 | 2018-02-21 | Janssen Pharmaceutica NV | Antibodies to quetiapine haptens and use thereof |
CN104736561B (zh) * | 2012-08-21 | 2018-06-12 | 詹森药业有限公司 | 帕潘立酮的抗体及其用途 |
PL2888592T3 (pl) | 2012-08-21 | 2018-03-30 | Janssen Pharmaceutica Nv | Przeciwciała względem kwetiapiny i ich zastosowania |
EP2888287A4 (en) * | 2012-08-21 | 2016-04-20 | Ortho Clinical Diagnostics Inc | ANTIBODIES AGAINST PALIPERIDONE HAPTENES AND THEIR USE |
WO2014080285A2 (en) | 2012-09-19 | 2014-05-30 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
AR096131A1 (es) | 2013-04-30 | 2015-12-09 | Otsuka Pharma Co Ltd | Preparado oral sólido que comprende aripiprazol y un método para producir un preparado oral sólido que comprende aripiprazol |
EP2838513B1 (en) * | 2013-04-30 | 2017-04-05 | Otsuka Pharmaceutical Co., Ltd. | Oral solid preparation comprising aripiprazole and method for producing oral solid preparation comprising aripiprazole |
US10525057B2 (en) | 2013-09-24 | 2020-01-07 | Otsuka Pharmaceutical Co., Ltd. | Method of providing aripiprazole to patients having impaired CYP2D6 or CYP3A4 enzyme function |
US9452131B2 (en) | 2014-03-20 | 2016-09-27 | Alkermes Pharma Ireland Limited | Aripiprazole formulations having increased injection speeds |
CN106794251B (zh) * | 2014-08-18 | 2020-12-29 | 阿尔科姆斯制药爱尔兰有限公司 | 阿立哌唑前体药物组合物 |
US10016415B2 (en) | 2014-08-18 | 2018-07-10 | Alkermes Pharma Ireland Limited | Aripiprazole prodrug compositions |
CA2959329C (en) * | 2014-08-25 | 2023-06-27 | Alkermes Pharma Ireland Limited | Crystallization process of aripiprazole derivatives in extended release formulations for treatment of schizophrenia |
WO2016189504A1 (en) * | 2015-05-28 | 2016-12-01 | Leiutis Pharmaceuticals Pvt Ltd | Non-lyophilized compositions of aripiprazole and methods of preparation thereof |
TWI584823B (zh) * | 2015-08-31 | 2017-06-01 | 諾瑞特國際藥業股份有限公司 | 具有延長的保存期限的阿立哌唑可注射懸浮液製劑 |
CN106474058B (zh) | 2015-08-31 | 2020-01-07 | 南京诺瑞特医药科技有限公司 | 具有延长的保质期的阿立哌唑可注射悬浮液制剂 |
JP6504019B2 (ja) * | 2015-10-27 | 2019-04-24 | 豊田合成株式会社 | 発光装置 |
US10435478B2 (en) | 2015-12-17 | 2019-10-08 | Janssen Pharmaceutica Nv | Antibodies to quetiapine and use thereof |
US10444250B2 (en) | 2015-12-17 | 2019-10-15 | Janssen Pharmaceutica Nv | Antibodies to risperidone and use thereof |
CN105663057A (zh) * | 2015-12-30 | 2016-06-15 | 中国药科大学 | 阿立哌唑长效混悬剂及其制备方法 |
EP3490529A1 (en) * | 2016-07-28 | 2019-06-05 | Mylan Laboratories Ltd. | Process for preparing sterile aripiprazole formulation |
US11273158B2 (en) | 2018-03-05 | 2022-03-15 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
CN110327296B (zh) * | 2019-08-06 | 2021-10-22 | 深圳市泛谷药业股份有限公司 | 一种阿立哌唑长效注射制剂及其制备方法 |
KR102486564B1 (ko) * | 2019-08-23 | 2023-01-19 | 주식회사 대웅테라퓨틱스 | 니클로사마이드 지연방출 조성물 및 이의 항바이러스 용도 |
US20230310417A1 (en) | 2020-03-30 | 2023-10-05 | Cipla Limited | Injectable aripiprazole formulation |
EP4125903A1 (en) * | 2020-04-01 | 2023-02-08 | Otsuka Pharmaceutical Co., Ltd. | Methods for dose initiation of aripiprazole treatments |
KR102606504B1 (ko) * | 2020-04-10 | 2023-11-29 | 주식회사 대웅테라퓨틱스 | 니클로사마이드를 포함하는 폐고혈압의 예방 및 치료용 조성물 |
CN115768407A (zh) * | 2020-05-21 | 2023-03-07 | 江苏先声药业有限公司 | 一种含依匹哌唑药物组合物及其制备方法 |
CN112656761B (zh) * | 2020-12-30 | 2023-09-08 | 河南合智医药科技有限公司 | 一种低刺激性阿立哌唑前药的油溶缓释注射制剂及其制备方法 |
EP4043008A1 (en) | 2021-02-15 | 2022-08-17 | Warszawskie Zaklady Farmaceutyczne Polfa S.A. | Method for the preparation of a pharmaceutical composition comprising aripiprazole |
HUP2100259A1 (hu) | 2021-07-07 | 2023-01-28 | Richter Gedeon Nyrt | Cariprazine tartalmú szabályozott hatóanyag-leadású injekciós készítmények |
CN115554253B (zh) * | 2022-10-14 | 2024-03-29 | 浙江圣兆药物科技股份有限公司 | 一种平稳释药的注射用阿立哌唑冻干制剂及其制备方法 |
GR1010624B (el) * | 2023-03-23 | 2024-01-30 | Φαρματεν Α.Β.Ε.Ε., | Φαρμακευτικο σκευασμα που περιλαμβανει αριπιπραζολη και μεθοδος για την παρασκευη αυτου |
GR1010656B (el) * | 2023-03-23 | 2024-03-21 | Φαρματεν Α.Β.Ε.Ε., | Φαρμακευτικο σκευασμα που περιλαμβανει εναν ατυπο αντιψυχωσικο παραγοντα και μεθοδος για την παρασκευη αυτου |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5006528A (en) * | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
CN1845721A (zh) * | 2003-08-06 | 2006-10-11 | 阿尔克姆斯第二控制治疗公司 | 阿立哌唑的给药方法 |
Family Cites Families (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB209551A (en) | 1922-11-20 | 1924-01-17 | William Mortimer Melmore | Improvements in or relating to petrol and other cans |
US4038389A (en) | 1975-05-07 | 1977-07-26 | The Upjohn Company | Medroxyprogesterone acetate compositions |
JPS54130587A (en) | 1978-03-30 | 1979-10-09 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
CA1209477A (en) | 1981-03-26 | 1986-08-12 | Bruce E. Haeger | Composition of matter comprising a lyophilized preparation of a penicillin derivative |
JPS5832899A (ja) | 1981-08-18 | 1983-02-25 | Takeda Chem Ind Ltd | オキセンドロン水性懸濁剤 |
US4352811A (en) | 1981-11-12 | 1982-10-05 | Hoechst-Roussel Pharmaceuticals Inc. | 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles |
IL68549A (en) * | 1983-05-03 | 1988-05-31 | Kit Medidont Ltd | Method and instrument for measuring moisture |
KR850004274A (ko) | 1983-12-13 | 1985-07-11 | 원본미기재 | 에리트로포이에틴의 제조방법 |
US4804663A (en) | 1985-03-27 | 1989-02-14 | Janssen Pharmaceutica N.V. | 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles |
JP2608788B2 (ja) * | 1988-10-31 | 1997-05-14 | 大塚製薬 株式会社 | 精神分裂病治療剤 |
JPH03212852A (ja) | 1990-01-18 | 1991-09-18 | Hitachi Electron Eng Co Ltd | 記録媒体カートリッジ搬送装置における送り機構 |
FR2663223B1 (fr) | 1990-06-14 | 1994-12-02 | Af Aplicaciones Far Lab | Forme galenique parenterale. |
ES2078447T3 (es) | 1990-06-15 | 1995-12-16 | Merck & Co Inc | Un procedimiento de cristalizacion para mejorar la estructura y el tamaño de los cristales. |
IT1244880B (it) | 1990-12-11 | 1994-09-12 | Torre A Farmaceutici | Formulazioni di amminoacidi liofilizzati contenenti glutammina, loro preparazione ed uso nell'alimentazione parenterale |
US6193983B1 (en) | 1992-06-01 | 2001-02-27 | The University Of Melbourne | Equine herpesvirus glycoproteins |
TW376319B (en) | 1993-04-28 | 1999-12-11 | Janssen Pharmaceutica Nv | Pharmaceutical composition containing risperidone pamoate and having a long acting activity for treating psychoses induced by the release of dopamine |
NZ276088A (en) | 1993-11-19 | 1999-07-29 | Janssen Pharmaceutica Nv | [(1,2-benzisoxazol-3-yl)-1-piperidinyl-alkyl-6,7,8,9-tetrahydro-4h- pyrido[1,2-a]-pyrimidin-4-one derivatives (ie risperidone) |
EP0762897B1 (en) | 1994-06-02 | 2003-04-02 | Elan Drug Delivery Limited | Method of preventing aggregation of proteins/peptides upon rehydration or thawing |
RU2082401C1 (ru) | 1994-08-18 | 1997-06-27 | Фармацевтическое акционерное общество "Ферейн" | Способ получения лекарственной формы комбинированного препарата |
US6165442A (en) | 1996-02-19 | 2000-12-26 | Nycomed Imaging As | Thermally stabilized ultrasound contrast agent |
TW487572B (en) | 1996-05-20 | 2002-05-21 | Janssen Pharmaceutica Nv | Aqueous suspensions of 9-hydroxyrisperidone fatty acid esters |
PT941066E (pt) | 1996-08-26 | 2004-03-31 | Transgene Sa | Complexos de lipido cationico - acido nucleico |
US6297231B1 (en) | 1996-10-28 | 2001-10-02 | Merck & Co., Inc. | Stabilized carbapenem antibiotic compositions and method of making |
GB9705588D0 (en) * | 1997-03-18 | 1997-05-07 | Anglia Research Foundation | Stable particle in liquid formulations |
GB9718986D0 (en) | 1997-09-09 | 1997-11-12 | Danbiosyst Uk | Controlled release microsphere delivery system |
UA72189C2 (uk) | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Фармацевтична композиція, що містить водну суспензію субмікронних ефірів 9-гідроксирисперидон жирних кислот |
DE69935433T2 (de) | 1998-07-30 | 2007-10-25 | Point Biomedical Corp., San Carlos | Neuer wirkstoffträger für die gefriertrocknung von wässrigen suspensionen von mikropartikeln |
DE19857609A1 (de) | 1998-12-14 | 2000-06-15 | Hannelore Ehrenreich | Verwendung von Erythropoietin zur Behandlung von cerebralen Ischämien des Menschen |
US6455526B1 (en) | 1998-12-16 | 2002-09-24 | Aventis Pharmaceuticals, Inc. | Biodegradable polymer encapsulated pharmaceutical compositions and method for preparing the same |
US6267989B1 (en) | 1999-03-08 | 2001-07-31 | Klan Pharma International Ltd. | Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions |
HUP0203624A3 (en) | 1999-12-09 | 2003-10-28 | Syngenta Participations Ag | Pyrazolecarboxamide and pyrazolethioamide as fungicide, intermediates, preparation and use thereof |
JP2001187735A (ja) * | 2000-01-05 | 2001-07-10 | Towa Yakuhin Kk | 安定なニコランジル含有粉末の製造法 |
US6559128B1 (en) | 2000-01-21 | 2003-05-06 | Northwestern University | Inhibitors of G protein-mediated signaling, methods of making them, and uses thereof |
RU2169574C1 (ru) | 2000-01-27 | 2001-06-27 | Кобатов Алексей Иванович | Способ получения биопрепарата и сухой биопрепарат |
AU2001233180A1 (en) | 2000-02-10 | 2001-08-20 | Alkermes Controlled Therapeutics, Inc. | Method of preparing a sustained release composition |
SK14842002A3 (sk) | 2000-03-27 | 2003-04-01 | The Scripps Research Institute | Inhibícia angiogenézy a rastu tumoru |
WO2001078687A1 (en) | 2000-04-18 | 2001-10-25 | Peptron Inc. | Injectable sustained release pharmaceutical composition and processes for preparing the same |
US6495164B1 (en) | 2000-05-25 | 2002-12-17 | Alkermes Controlled Therapeutics, Inc. I | Preparation of injectable suspensions having improved injectability |
JP2002241284A (ja) * | 2001-02-16 | 2002-08-28 | Towa Yakuhin Kk | 全身投与用アルガトロバン注射液 |
MY129350A (en) | 2001-04-25 | 2007-03-30 | Bristol Myers Squibb Co | Aripiprazole oral solution |
JP2003063965A (ja) * | 2001-06-13 | 2003-03-05 | Otsuka Pharmaceut Factory Inc | 注射用シロスタゾール水性製剤 |
CN100350977C (zh) | 2001-06-14 | 2007-11-28 | 大塚制药株式会社 | 药物组合物 |
DE60224293T2 (de) | 2001-09-21 | 2008-12-11 | Egalet A/S | Feste dispersionen mit kontrollierter freisetzung von carvedilol |
MY138669A (en) * | 2001-09-25 | 2009-07-31 | Otsuka Pharma Co Ltd | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
AR033485A1 (es) * | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | Sustancia medicinal de aripiprazol de baja higroscopicidad y proceso para la preparacion de la misma |
ITMI20020808A1 (it) | 2002-04-17 | 2003-10-17 | Chiesi Farma Spa | Procedimento per la preparazione di una sospensione sterile di particelle di beclometasone dipropionato da somministrare per inalazione |
GB0216416D0 (en) | 2002-07-15 | 2002-08-21 | Novartis Ag | Organic compounds |
WO2004006959A1 (en) * | 2002-07-16 | 2004-01-22 | Elan Pharma International, Ltd | Liquid dosage compositions of stable nanoparticulate active agents |
WO2004017897A2 (en) * | 2002-08-20 | 2004-03-04 | Bristol-Myers Squibb Company | Aripiprazole complex formulation and method |
WO2004064752A2 (en) * | 2003-01-22 | 2004-08-05 | Alkermes Controlled Therapeutics, Inc. | Method of preparing sustained release microparticles |
US6987111B2 (en) | 2003-08-06 | 2006-01-17 | Alkermes Controlled Therapeutics, Ii | Aripiprazole, olanzapine and haloperidol pamoate salts |
JP4836797B2 (ja) * | 2003-10-23 | 2011-12-14 | 大塚製薬株式会社 | 放出制御性無菌注射アリピプラゾール製剤および方法 |
AU2004285595A1 (en) | 2003-10-31 | 2005-05-12 | Point Biomedical Corporation | Reconstitutable microsphere compositions useful as ultrasonic contrast agents |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5006528A (en) * | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
CN1845721A (zh) * | 2003-08-06 | 2006-10-11 | 阿尔克姆斯第二控制治疗公司 | 阿立哌唑的给药方法 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019218409A1 (zh) | 2018-05-16 | 2019-11-21 | 丽珠医药集团股份有限公司 | 一种阿立哌唑缓释微球及其制备方法 |
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